Methods of electrospray chemical synthesis

ABSTRACT

The present invention relates to methods of production of chemical bonds and subsequent molecules by electrospray ionization for use in chemical synthesis and expedited organic chemical reactions.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a Division of co-pending U.S. patent applicationSer. No. 13/144,832, filed Jul. 15, 2011, which is a Section 371International Application No. PCT/CA2010/000063, filed Jan. 15, 2010,which was published in the English language on Jul. 22, 2010, underInternational Publication No. WO 2010/081236 A1, which claims thebenefit of U.S. Provisional Patent Application No. 61/145,186, filedJan. 16, 2009, the disclosures of which are incorporated herein byreference.

BACKGROUND OF THE INVENTION

The present invention relates to methods of production of chemical bondsand subsequent molecules by electrospray ionization and the design of anelectrospray chemical synthesizer, for use in chemical synthesis andexpedited chemical reactions.

A typical electrospray source is a two-electrode, controlled-currentelectrochemical flow cell. The three steps involved during electrosprayionization (ESI) are: 1) generation and charging of ES droplets 2)evaporation of droplets 3) production of gas-phase ions. Electrospraytechnology is commonly used in mass spectrometry, colloid thrusters,polymer coating, nanospray direct writing and the paint industry. Anelectrospray (ES) is a very mild way of ionizing molecules for detectionin the mass spectrometer (MS). Oxidation and reduction reactions havebeen reported in an electrospray ion source in the works of Van Berkel(Van Berkel, J Am Soc Mass Spectrom, 2000, 11(11): 951-60; Van Berkel etal., Anal Chem, 2002, 74(19): 5047-56) Van Berkel et al., Anal Chem,2007, 79(15): 5510-20). All documents cited in this application areincorporated by reference. Chemical reactions occurring in theelectrospray capillary. In this case, molecules react with the surfaceof the capillary tube (usually coated with a metal, e.g. palladium orgold) to yield various products. Under a variety of reaction conditionsthe solution mixture in the electrospray can be subjected to redoxchemistry. Van Berkel's works verify this statement due to reportedelectrolysis and pH changes in electrospray ionization (Van Berkel etal. Int J Mass Spectrom. Ion Processes, 1997, 162: 55-62). Theelectrospray source has been used for initiation of thermally inducedreactions; however, these reactions occur at the hot surface of theelectrospray source and not in the electrospray cone (Griep-Raming andMetzger, Anal Chem, 2000, 72(22): 5665-8). Methods of elimination ofoxidation or reduction reactions on conductive surfaces in the samplesolution flow channel during electrospray ionization have beeninvestigated (Whitehouse and White, PCT/US2005/017573). All previousinvestigations have been focused on the analytical aspect of moleculesand none have suggested utilization of electrospray for chemicalsynthesis.

The present invention provides methods utilizing electrospray fororganic syntheses which are both efficient and have a lowerenvironmental impact compared to conventional methods.

BRIEF SUMMARY OF THE INVENTION

The present invention provides a novel method of using electrosprayionization for organic chemical synthesis, and in particular, thesynthesis of esters, amides, amines and alcohols. The present inventionfurther provides an electrospray chemical synthesis system for use insuch methods.

In one aspect, provided is a method of preparing and recovering anoxidation reaction product, comprising passing a reactant through anelectrospray to provide an ionized reaction mixture and recovering saidreaction product from the ionized reaction mixture.

In a further aspect, provided is a method of preparing and recovering areduction reaction product comprising passing a reactant through anelectrospray to provide an ionized reaction mixture and recovering saidreaction product from the ionized reaction mixture.

In a further aspect, provided is a method of preparing and recovering analdol condensation reaction product comprising passing an enol compoundand a carbonyl compound through an electrospray to provide an ionizedreaction mixture and recovering said reaction product from the ionizedreaction mixture.

In a further aspect, provided is a method of preparing and recovering anamide comprising passing a carboxylic acid and an amine through anelectrospray to provide an ionized reaction mixture and recovering saidamide from the ionized reaction mixture.

In a further aspect, provided is a method of preparing and recovering asecondary amine comprising passing a nitro compound through anelectrospray to provide an ionized reaction mixture and recovering saidsecondary amine from the ionized reaction mixture.

In a further aspect, provided is a method of preparing and recovering animine comprising passing an amine, and an aldehyde through anelectrospray to provide an ionized reaction mixture and recovering iminefrom the ionized reaction mixture.

In a further aspect, provided is a method of preparing and recovering analkyl amine, comprising passing a amine and an alkyl halide through anelectrospray to provide an ionized reaction mixture and recovering saidalkyl amine from the ionized reaction mixture.

In a further aspect, provided is a method of preparing and recoveringreaction product resulting from the hydrolysis of an ester comprisingpassing an ester through an electrospray to provide an ionized reactionmixture and recovering said reaction product from the ionized reactionmixture.

In a further aspect, provided is a method of preparing and recovering amono or di acetal comprising passing an aldehyde and alcohol through anelectrospray to provide an ionized reaction mixture and recovering saidmono or di acetal from the ionized reaction mixture.

In a further aspect, provided is a method of preparing and recovering analcohol and carboxylic acid comprising passing an ester through anelectrospray to provide an ionized reaction mixture and recovering saidalcohol and carboxylic acid from the ionized reaction mixture.

In a further aspect, provided is a method of preparing and recovering analcohol oxidation product comprising passing an alcohol through anelectrospray to provide an ionized reaction mixture and recovering saidalcohol oxidation product from the ionized reaction mixture.

In a further aspect, provided is a method of preparing and recovering areaction product resulting from the reduction of nitro compound,comprising passing a nitro compound through an electrospray to providean ionized reaction mixture and recovering the reduced product from theionized reaction mixture.

In a further aspect, provided is a method of preparing and recovering aSuzuki reaction product, comprising passing aryl- or vinyl-boronic acidwith an aryl- or vinyl-halide and traces of Pd catalyst through anelectrospray to provide an ionized reaction mixture and recovering saidreaction product from the ionized reaction mixture.

In a further aspect, provided is a method of preparing and recovering aHeck reaction product, comprising passing aryl or vinyl halide with analkene in the presence of Pd catalyst through an electrospray to providean ionized reaction mixture and recovering said reaction product fromthe ionized reaction mixture.

In a further aspect, provided is a method of preparing and recovering aproduct of elimination comprising passing an organic molecule containinga leaving group through an electrospray to provide an ionized reactionmixture and recovering said reaction product from the ionized reactionmixture.

In a further aspect, provided is a method of preparing and recovering anester comprising passing an acid and an alcohol through an electrosprayto provide an ionized reaction mixture and recovering said reactionproduct from the ionized reaction mixture.

In an embodiment, the capillary voltage of the electrospray is between1.0 to 4.0 kV.

In a further embodiment, the capillary voltage of the electrospray is atleast 3.0 kV.

In a further embodiment, the capillary voltage of the electrospray is atleast 4.0 kV.

In a further embodiment, the cone voltage of the electrospray is lessthan 100V.

In a further embodiment, the cone voltage of the electrospray is lessthan 30V.

In a further embodiment, the reaction product is enriched by passing theionized reaction mixture through a second electrospray.

In a further aspect, provided is a chemical synthesis system comprising:an injector coupled to an electrospray for introducing chemicalcompounds into the electrospray; and a collection system for receivingchemical compounds expelled by the electrospray; wherein said collectionsystem is in fluid communication with said injector for reintroducingsaid chemical compounds into the electrospray.

In a further embodiment, the collection system is in fluid communicationwith a liquid chromatographic apparatus for separation of unreactedchemical compounds and reacted chemical compounds.

In a further embodiment, the liquid chromatographic apparatus is influid communication with said injector for transfer of unreactedchemical compounds to said injector for reintroduction into theelectrospray.

In a further embodiment, the electrospray is coupled to a massspectrometer.

BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS

The foregoing summary, as well as the following detailed description ofthe invention, will be better understood when read in conjunction withthe appended drawings. For the purpose of illustrating the invention,there are shown in the drawings embodiments which are presentlypreferred. It should be understood, however, that the invention is notlimited to the precise arrangements and instrumentalities shown.

In the drawings:

FIG. 1 shows a schematic representation of the electrospray ionizationprocess for use in methods of chemical synthesis.

FIG. 2 shows the typical design of an electrospray chemical synthesizercomprising an heated injection system (1), a power source (2), nebulizer(3), collection system (4), laser energizer (5), microwave source (6),orifice ring connected to a secondary power source (7) and a computerinterface (8).

FIGS. 3A, 3B, and 3C show ESI-MS Spectra of 2-pyridylacetic acid inmethanol at different capillary voltage. The signal corresponding tomethyl ester increases as the capillary voltage is increased from +1 kVto +4 kV (example 1).

FIGS. 4A, 4B, and 4C show ESI-MS Spectra of 2-pyridylacetic acid inmethanol at constant high capillary voltage (3 kV) but different conevoltage (example 2)

FIGS. 5A, 5B, and 5C show ESI-MS Spectra of 2-pyridylacetic acid inmethanol containing trifluoroacetic acid at different capillary voltage(example 3).

FIGS. 6A, 6B, and 6C show ESI-MS Spectra of 2-pyridylacetic acid inmethanol containing trifluoroacetic acid at fixed capillary voltage butdifferent cone voltage (example 4).

FIGS. 7A, 7B, and 7C show ESI-MS Spectra of 2-pyridylacetic acidhydrochloride in ethanol at fixed cone but different capillary voltage(example 5).

FIGS. 8A, 8B, 8C, and 8D show ESI-MS Spectra of 2-pyridylacetic acid inethanol at constant high capillary voltage (3 kV) but different conevoltage (example 6).

FIG. 9A shows ESI-MS (positive mode) of 5-bromo-2-nitropyridine showingthe formation of amine from a nitro group at high cone voltage (example11).

FIG. 9B shows ESI-MS (positive mode) of 5-bromo-2-nitropyridine showinga decrease in the formation of an amine from a nitro group as the conevoltage is reduced from 100 V (FIG. 9A) to 80V (example 11).

FIG. 9C shows ESI-MS (positive mode) of 5-bromo-2-nitropyridine showingno amine formation from a nitro group at a cone voltage of 60Vindicating that the reduction of the nitro group occurs at a conevoltage greater than 60 volts (example 11).

FIG. 9D shows ESI-MS (positive mode) of 5-bromo-2-nitropyridine showingno amine formation as the desolvation temperature is lowered from 500°C. to 200° C. demonstrating the importance of the desolvationtemperature on reduction of the nitro group (example 11).

FIG. 9E shows ESI-MS (positive mode) of 5-bromo-2-nitropyridine showingno amine formation from a nitro group at a cone voltage of 30V but athigher source temperature (150° C.) indicating that the sourcetemperature has a comparatively minor role in the reduction of a nitrogroup compared to desolvation temperature and cone voltage (example 11).

FIG. 9F shows ESI-MS (positive mode) of 5-bromo-2-nitropyridine showingno amine formation from a nitro group at a cone voltage of 30V but athigher source temperature (150° C.) and capillary voltage (4.0 KV)showing that source temperature and capillary voltage have minor role inreduction compared to the desolvation temperature and cone voltage(example 11).

FIG. 10 shows ESI-MS (positive mode) of an aldol formed from thereaction of 4-pyridinecarboxaldehyde with acetone in the electrospray(example 12).

FIG. 11A shows ESI-MS (positive mode) of ethyl and butyl ester formedfrom 2-pyridyl acetic acid and butanol in the electrospray at a highcone voltage (100V) (example 10).

FIG. 11B shows ESI-MS (positive mode) of 2-pyridyl acetic acid inbutanol. No ester formation is seen at a cone voltage of 20V (example10).

FIG. 12 shows ESI-MS (positive mode) of methyl and 2-propanol ester from2-pyridyl acetic acid and 2-propanol in the electrospray at a high conevoltage (94V) (example 9).

FIG. 13A shows ESI-MS (positive mode) formation of an amide bond from2-amino-5-bromopyridine and acetic anhydride in the electrospray. Thesignals at 214 and 216 are due to the product while signals at 214 and216 are due to 2-amino-5-bromopyridine and acetic anhydride adduct(example 13).

FIG. 13B shows ESI-MS (positive mode) formation of an amide bond from2-amino-5-bromopyridine and acetic anhydride in the electrospray. Thesignals at 214 and 216 are due to the product while signals at 214 and216 are due to 2-amino-5-bromopyridine and the acetic anhydride adduct.The signal due to the adduct is enhanced at high cone voltage formation(example 13).

FIG. 14A shows ESI-MS (negative mode) formation of an amide bond from(2S)-2-amino-3-(4-(hydroxyhydrophosphoryl)phenyl)propanoic acid anddiethylamine in the electrospray. The signal at 283 is due to theproduct formed at a high voltage (161 V) (example 14).

FIG. 14B shows ESI-MS (negative mode) formation of an amide bond from(2S)-2-amino-3-(4-(hydroxyhydrophosphoryl)phenyl)propanoic acid anddiethylamine in the electrospray. The product signal intensity at 283.2is decreased as the cone voltage is lowered from 161 volts (FIG. 14A) to30 volts (example 14).

FIG. 15A shows ESI-MS (negative mode) hydrolysis of an ester from3-formylphenoxyacetic acid in the electrospray. The hydrolysis isfavored at a high cone voltage (100 volts) (example 15).

FIG. 15B shows ESI-MS (negative mode) hydrolysis of an ester from3-formylphenoxyacetic acid in the electrospray. The hydrolysis productis increased as the desolvation temperature is also increased from 200°C. to 500° C. Thus hydrolysis is favored at a high desolvationtemperature and high cone voltage (example 15).

FIG. 15C shows ESI-MS (negative mode) of hydrolysis of an ester from3-formylphenoxyacetic acid in the electrospray. The hydrolysis signal isdecreased as the cone voltage is lowered to 20 V and desolvationtemperature is 200° C. (example 15).

FIG. 16A shows ESI-MS (positive mode) of the formationbis(5-bromopyridin-2-yl)amine from 2-nitro 5-bromo pyridine in theelectrospray (example 16).

FIG. 16B shows ESI-MS (positive mode) of the formationbis(5-bromopyridin-2-yl)amine from 2-nitro 5-bromo pyridine in theelectrospray. The product is increased as cone voltage is increased from50 volts (FIG. 16A) to 150 volts (example 16).

FIG. 16C shows ESI-MS (negative mode) of the formation of an imine fromthe reaction of 4-bromoaniline and 2-formylphenoxyacetic acid in theelectrospray. The hydrolyzed product of both the imine product and2-formylphenoxyacetic acid is also seen (example 16).

FIG. 16D shows ESI-MS (negative mode) of the formation of an imine fromthe reaction of 4-bromoaniline and 2-formylphenoxyacetic acid in theelectrospray. The product is increased as the cone voltage is increasedto 100 volts (example 16).

FIG. 16E shows ESI-MS (positive mode) of the formation of an imine fromthe reaction of 4-bromoaniline and 2-formylphenoxyacetic acid in theelectrospray (example 16).

FIG. 17A shows ESI-MS (negative mode) of the formation of diethylacetalfrom the reaction of ethanol and 2-formylphenoxyacetic acid in theelectrospray (example 18).

FIG. 17B shows ESI-MS (negative mode) of the formation of diethylacetalfrom the reaction of ethanol and 2-formylphenoxyacetic acid in theelectrospray. The formation of diethylacetal is decreased as thedesolvation temperature is decreased from 500° C. (FIG. 17A) to 400° C.despite increasing the cone voltage from 40 volts to 60 volts (example18).

FIG. 17C shows ESI-MS (negative mode) of the formation of diethylacetalfrom the reaction of ethanol and 2-formylphenoxyacetic acid in theelectrospray. High cone voltage favors monoethylacetal overdiethylacetal (example 18).

FIG. 18A shows ESI-MS (negative mode) of the formation of dimethylacetalfrom the reaction of methanol and 2-formylphenoxyacetic acid in theelectrospray (example 19).

FIG. 18B shows ESI-MS (negative mode) of the oxidation of2-formylphenoxyacetic acid in the electrospray using a cone voltage of40 volts and desolvation temperature of 200° C.

(example 19).

FIG. 19A shows ESI-MS spectrum (positive mode) of formation of butyl andethyl ester from of 2-pyridylacetic acid in 1-butanol duringelectrospray at cone voltage of 100 V. The ethyl ester was formed byelimination reaction from the butyl ester. This is an example of 2-stepsynthesis in electrospray (example 28).

FIG. 19B shows ESI-MS spectrum (positive mode) of 2-pyridylacetic acidin 1-butanol during electrospray at cone voltage of 20V. No esterproduct was detected at low cone voltage (example 28).

FIG. 20 shows ESI-MS spectrum (positive mode) of formation of propyl andmethyl ester from of 2-pyridylacetic acid in 2-propanol duringelectrospray at cone voltage of 97 V. The methyl ester was formed byelimination reaction from the propyl ester. This is an example of 2-stepsynthesis in electrospray (example 29).

DETAILED DESCRIPTION OF THE INVENTION

The possibility of using electrospray for preparatory organic synthesiswas discovered during analysis of amino acids in methanol solvent byES-MS techniques where the corresponding methyl ester products wereidentified. Interestingly, the reaction between carboxylic acid (aminoacid) and alcohol (methanol) functional groups typically requires thepresence of a catalyst. In the above ES-MS case, however, no catalystwas required. These results suggest the potential for electrospraytechniques to carry out chemical reactions using mild conditions withoutthe need for any catalyst.

Further experimentations showed that electrospray can also expediteother classes of reactions such as amide formation, oxidation,reduction, Schiff base formation, elimination and condensationreactions.

Organic chemistry lies at the center of the pharmaceutical and chemicalindustries. Despite enormous advances in the field, however, manychemical reactions are slow, low-yielding, and non-selective. Aconsequence of these inefficiencies is significant chemical waste,low-productivity, and loss of revenue. The traditional techniques usedto accelerate chemical reactions are to apply heat, UV irradiation,and/or to add a catalyst (usually an expensive, toxic metal) to thereaction vessel. In many cases, however, these methods fail to achievetheir desired goal. Developing a process that can reduce chemical waste,energy consumption, and reaction by-products would represent asignificant advance in the pharmaceutical and chemical industries.

The key innovative aspect of the Electrospray Chemical Synthesizer is toutilize electrospray for chemical synthesis. The reactivity patterns ofmolecules in the electrospray differ from molecules in the solutionphase (where conventional organic synthesis occurs) thereby opening thepossibility for improved reactivity profiles.

A scientific basis for using electrospray for chemical synthesis is theobservation that chemical reactions can proceed in the electrospray withthe possibility of isolating and purifying the desired chemicalproducts. Chemical reactions occurring in the electrospray can beinfluenced and fine-tuned by a wide range of parameters such ascapillary and cone voltages, and source and desolvation temperaturesetc.

The advantages offered by the Electrospray Chemical Synthesizer are a)the ability to synthesize target compounds in a shorter period of timecompared to conventional techniques, b) the ability to synthesize targetcompounds not easily prepared compared by conventional techniques, andc) the elimination of expensive, toxic, metal-based catalysts.Electrospray Chemical synthesis is a part of green chemistry innovation.

The present invention provides a novel method of using electrosprayionization for organic chemical synthesis, and in particular, thesynthesis of esters, amide, amines, and alcohol. The present inventionfurther provides an electrospray chemical synthesis system for use insuch methods. The presently disclosed methods and electrospray chemicalsynthesis system provides for the efficient production of organicproducts as reactions occur in both the electrospray capillary and conethat provide the activation energy for reactions. The electrospraychemical synthesis system can be used for production of chemicalcompounds from a smaller scale to industrial production. It can be usedin a wide range of organic reactions, including but not limited topalladium catalyzed coupling, aldol condensation, esterification,photochemistry, carbon-carbon bond formation, oxidation reductionreactions, protection and deprotection of various functional groups,inorganic compound formations and reactions which would not be possiblewith conventional techniques.

The disclosed methods and electrospray chemical synthesis systemrepresent a major innovation in green chemistry creating a brand newtechnology for chemical synthesis. The disclosed methods andelectrospray chemical synthesis system have a lower environmental impactcompared to conventional synthesis methods as the increase in theefficiency of chemical synthesis allows for diminished quantities ofsolvents and chemicals and consequentially a reduction in toxic wastes.Reactions which usually have long reaction times and require expensiveand toxic catalysts can be completed in a few seconds using theelectrospray synthesis method.

The term “electrospray chemical synthesis process” refers to the processof electrospray ionization used to conduct chemical synthesis reactions.In a preferred embodiment, this process is represented schematically inFIG. 1. The process involves introduction of reacting species to theelectrospray acting as a chemical synthesizer, optimization ofelectrospray parameters and collection of the products. The electrosprayparameters include capillary voltage, cone voltage, and temperature. Theprocess may be repeated until the starting material is convertedcompletely to the final product. The apparatus can be linked to acomputer interface.

The terms “Electrospray Chemical Synthesizer” and “ECS”, can be usedinterchangeably herein, and refer to the device used for electrospraychemical synthesis. The electrospray synthesizer may consist of aninjection system, power sources, a collection system and a computerinterface. A laser source is used for photo-initiating reactions. Theelectrospray chemical synthesizer has the capability of introducingmultiple reagents into the electrospray source and has the capability ofrecycling the formed product back to the electrospray if the reaction isnot complete during the electrospray process.

The term “electrospray cone” as used herein refers to the locus ofchemical bond formation located at tip of the capillary as can be seenin FIG. 2.

The terms “ESI-MS” and “ES-MS”, are used interchangeably herein andrefer to the electrospray ionization chemical synthesis process followedby mass spectrometry.

The term “electrospray ionization” refers to energizing molecules in theelectrospray plume and the resulting energized molecules may or may notbe fully ionized.

The terms “bond”, “chemical bond” and “chemical linkage”, are usedinterchangeably herein and refer to ionic or covalent interactions, orthe like, between atoms and can include, but are not limited to bondsbetween carbon, oxygen, nitrogen, hydrogen, halogens, metals, silicon,boron, phosphorus, aluminum, selenium, arsenic and sulfur.

Methods of Electrospray Chemical Synthesis

Generally speaking, ester and amide formation are slow and requireactivation using various catalysts, however no catalyst was requiredduring electrospray and hence electrospray can be used as a mild sourceof reacting two molecules which would otherwise require harshconditions. The extent of formation of ester shows dependence onelectrospray conditions such as capillary voltage, etc. The ester isformed during the electrospray condition and not in the MS thusproviding a novel synthesis method. For example ES-MS of phenylalaninein methanol shows phenylalanine methyl ester and the intensity of thesignal is dependent upon the capillary voltage. Phenylalanine dissolvedin ethanol shows corresponding ethyl ester signals. It has also beenobserved that organic acid dissolved in ethylamine also shows the amideformation.

The present inventors are the first to use electrospray ionization forchemical synthesis, and in particular, for the synthesis of esters. Thepresent inventors found that when a solution of corresponding acid wasdissolved in an appropriate alcohol and directly infused to the ESI-MSat optimum condition, it was possible to obtain the maximum yield of theester. From various ESI-MS experiments it was concluded that theformation of ester strongly depends upon the temperature of the source,desolvation temperature, cone voltage, the volume of infusion, and thecapillary voltage.

The present invention provides novel methods which utilize electrosprayfor preparing organic compounds and in particular, esters. As usedherein, the term “electrospray chemical synthesis” refers to the processof electrospray ionization used to conduct chemical synthesis reactions.This process is represented schematically in FIG. 1.

It has been determined that by controlling the capillary voltage, conevoltage and desolvation temperature of the electrospray, the synthesisof organic compounds can be optimized. The chemical synthesis mayinvolve the formation of a chemical bond or linkage between reactants toprovide a desired product. The terms “bond”, “chemical bond” and“chemical linkage”, are used interchangeably herein and refer to ionicor covalent interactions, or the like, between atoms and can include,but are not limited to bonds between carbon, oxygen, nitrogen, hydrogen,halogens, metals, silicon, boron, phosphorus, aluminum, selenium,arsenic and sulfur.

In one embodiment, the present invention provides a method of preparingand recovering an oxidation reaction product, comprising passing areactant through an electrospray to provide an ionized reaction mixtureand recovering said reaction product from the ionized reaction mixture.

In another embodiment, the present invention provides a method ofpreparing and recovering a reduction reaction product, comprisingpassing a reactant through an electrospray to provide an ionizedreaction mixture and recovering said reaction product from the ionizedreaction mixture.

In another embodiment, the present invention provides a method ofpreparing and recovering an aldol condensation reaction productcomprising passing an enol compound and a carbonyl compound through anelectrospray to provide an ionized reaction mixture and recovering saidreaction product from the ionized reaction mixture.

In another embodiment, the present invention provides a method ofpreparing and recovering an amide comprising passing a carboxylic acidand an amine through an electrospray to provide an ionized reactionmixture and recovering said amide from the ionized reaction mixture.

In another embodiment, the present invention provides a method ofpreparing and recovering a secondary amine comprising passing a nitrocompound through an electrospray to provide an ionized reaction mixtureand recovering said secondary amine from the ionized reaction mixture.

In another embodiment, the present invention provides a method ofpreparing and recovering an imine comprising passing an amine, and analdehyde through an electrospray to provide an ionized reaction mixtureand recovering imine from the ionized reaction mixture.

In one embodiment, the present invention provides a method of preparingand recovering an alkyl amine, comprising passing an amine and an alkylhalide through an electrospray to provide an ionized reaction mixtureand recovering said reaction product from the ionized reaction mixture.

In another embodiment, the present invention provides a method ofpreparing and recovering reaction product resulting from the hydrolysisof an ester comprising passing an ester and alcohol through anelectrospray to provide an ionized reaction mixture and recovering saidreaction product from the ionized reaction mixture.

In another embodiment, the present invention provides a method ofpreparing and recovering a mono or di-acetal comprising passing analdehyde and alcohol through an electrospray to provide an ionizedreaction mixture and recovering said mono or di-acetal from the ionizedreaction mixture.

In another embodiment, the present invention provides a method ofpreparing and recovering a ketal comprising passing a ketone and alcoholthrough an electrospray to provide an ionized reaction mixture andrecovering said mono or di-ketal from the ionized reaction mixture.

In another embodiment, the present invention provides a method ofpreparing and recovering a carboxylic acid comprising passing an esterthrough an electrospray to provide an ionized reaction mixture andrecovering said alcohol and carboxylic acid from the ionized reactionmixture.

In another embodiment, the present invention provides a method ofpreparing and recovering an oxidation product comprising passing analdehyde or alcohol through an electrospray to provide an ionizedreaction mixture and recovering said carboxylic acid from the ionizedreaction mixture.

In another embodiment, the present invention provides a method ofpreparing and recovering a reaction product resulting from the alkyationof an amine, comprising passing an amine and alkyl halide through anelectrospray to provide an ionized reaction mixture and recovering saidreaction product from the ionized reaction mixture.

In another embodiment, the present invention provides a method ofpreparing and recovering a Suzuki reaction product, comprising passingaryl- or vinyl-boronic acid with an aryl- or vinyl-halide, in thepresence of a Pd catalyst through an electrospray to provide an ionizedreaction mixture and recovering said reaction product from the ionizedreaction mixture.

In another embodiment, the present invention provides a method ofpreparing and recovering a Heck reaction product, comprising passing analkene with an aryl or alkenyl halide, in the presence of a Pd catalystthrough an electrospray to provide an ionized reaction mixture andrecovering said reaction product from the ionized reaction mixture.

It will be appreciated that the choice of reactants will depend on thedesired reaction product. As compared to conventional synthesis methods,the use of expensive and/or toxic catalysts is not required. In general,the desired reactants will be dissolved in a suitable solvent, passedthrough the electrospray and the resulting ionized reaction mixturecollected and the desired reactant collected.

The synthesis of the desired reaction product is influenced by adjustingthe capillary voltage of the electrospray, the cone voltage of theelectrospray and the desolvation temperature. The optimum ionizationconditions can be readily determined by conducting small scale reactionsusing an electrospray coupled to a mass spectrometer to monitor theresulting products. By determining the optimum ionization conditions,the large scale production is implemented using the electrospraychemical synthesizer system discussed in greater detail below. Inanother embodiment, the inside of the capillary can be coated with animmobilized catalyst for assisting the desired chemical reaction.

The desired reaction product can be recovered from the ionizationreaction mixture using conventional methods known in the art such asliquid chromatographic methods. The concentration of the desiredreaction product can be enriched by collecting the ionization reactionmixture and passing the reaction mixture through a second electrosprayto catalyze the reaction of previously unreacted compounds. This stepcan be repeated multiple times to maximize recovery of the desiredproduct.

In another embodiment, the present invention provides a method ofpreparing and recovering an ester comprising passing an acid and analcohol through an electrospray to provide an ionized reaction mixtureand recovering said reaction product from the ionized reaction mixture.It will be appreciated that the choice of the acid and the alcohol willdepend on the desired end product. As discussed above, the optimumionization conditions can be determined by conducting small scalereactions using an electrospray coupled to a mass spectrometer tomonitor the resulting products.

In preferred embodiments of the method, esterification is maximized whenthe capillary voltage of the electrospray are relatively high ascompared to values used during analytical applications. The capillaryvoltage of the electrospray is preferably between 1 and 4.0 mV. In afurther preferred embodiment, the capillary voltage of the electrosprayis 3.0 mV. In a still more preferred embodiment, the capillary voltageof the electrospray is 4.0 mV.

In preferred embodiments of the method, esterification is maximized whenthe cone voltage of the electrospray will be relatively high as comparedto values used during analytical applications. The cone voltage of theelectrospray is preferably less than 40 V. In a further preferredembodiment, the cone voltage of the electrospray less than 30 V.

The methods of the present invention can be practiced using conventionalelectrosprays known in the art. For improved efficiency and ease of use,an automated chemical synthesis system can be employed. The chemicalsynthesis system can comprise an injector coupled to an electrospray forintroducing chemical compounds into the electrospray; and a collectionsystem for receiving chemical compounds expelled by the electrospray. Toallow for maximum product yield, unreacted compounds can be recycledback to the electrospray for ionization. The chemical synthesis systemcan be configured so that the collection system is in fluidcommunication with the injector so that unreacted compounds can bereintroduced into the electrospray. The chemical synthesis system can becontrolled with a computer interface which controls the injection ofchemical compounds into the electrospray, the operation of theelectrospray and the recycling of unreacted compounds.

An example of an electrospray chemical synthesizer system which can beused to practice the methods of the present invention is shown in FIG.2. In one embodiment, the electrospray chemical synthesizer systemcomprises a heated injection system (1), a power source (2), nebulizer(3), collection system (4), laser energizer (5), microwave source (6),orifice ring connected to a secondary power source (7) and a computerinterface (8).

In a further embodiment the injection system can comprises agravitational or pump driven syringe capable of delivering powder and/orliquid samples to an electrode of tubular, porous flow-through, planarflow-by, porous flow or other configuration for optimal efficiency. Thepower source preferably source comprises power supply capable ofgenerating potential difference of several kilovolts. The electricalconfiguration of electrospray chemical synthesizer can be a grounded orfloated system.

In use, the desired chemical reactants are transferred into theinjection system and permitted to interact. The contents of theinjection system are then expelled through the electrospray capillarywhile they are subjected to power sources permitting the formation ofthe spray which exits the electrospray cone. The capillary can be madeof metal or inorganic polymeric or other conducting material ofdifferent bore size. The spray can be subjected to microwave and laserfor additional energizing source. The spray is then free to contact acollection system for recovery of the desired product. The collectionsystem can comprise an enclosed vessel capable of isolating the productin an inert or evacuated environment.

In further embodiments of the invention, the collection system may becoupled with means for separating reacted and unreacted compounds. Forexample, the collection system may be in fluid communication with aliquid chromatographic apparatus capable of separating the collectedionization mixture into discrete fractions. Fractions containing thedesired end product can be directed to a storage vessel and fractionscontaining unreacted compounds can be redirected to the injection systemfor reintroduction into the electrospray for repeated ionization. Infurther embodiments of the invention, chemical synthesis system mayinclude a mass spectrometer for real time analysis of the chemicalsynthesis to ensure that the desired product is being produced.

Although the invention has been described with reference to illustrativeembodiments, it is to be understood that the invention is not limited tothese precise embodiments, and that various changes and modification areto be intended to be encompassed in the appended claims.

EXAMPLES Example 1 Electrospray Chemical Synthesis with VariableCapillary Voltage

8.8 mg of 2-pyridylacetic acid hydrochloride was dissolved in 19.72 mlof methanol and ES-MS spectrum were generated at a constant cone voltageof 30V and a variety of capillary voltage values, more specifically1.00, 3.00 and 4.00 kV, as can be seen in FIGS. 3A, B and C,respectively. The esterification process is favored at high capillaryvoltage. ESI-MS experiments also show that at higher cone voltage boththe ester and the acid disintegrate.

Example 2 Electrospray Chemical Synthesis with Variable Cone Voltage

8.8 mg of 2-pyridylacetic acid hydrochloride was dissolved in 19.72 mlof methanol and ESI-MS spectrum were generated at a constant capillaryvoltage of 3.00 kV and a variety of cone voltage values, morespecifically 40, 60 and 80 V, as can be seen in FIGS. 4A, B and C,respectively. Both esters and acid disintegrate at high cone voltage(>40 V).

Example 3 Electrospray Chemical Synthesis with Variable CapillaryVoltage in the presence of TFA

8.8 mg of 2-pyridylacetic acid hydrochloride was dissolved in 19.72 mlof methanol and ESI-MS spectrum were generated at a constant conevoltage of 40 V and a variety of capillary voltage values, morespecifically 1.00, 3.00 and 5.00 kV, in the presence of TFA, as can beseen in FIGS. 5A, B and C, respectively. Acids are commonly used as acatalyst for reactions between acid and alcohol. The acid showedimprovement in the formation of esters. Thus ester signal relative toacid at 1 kV was increased in presence of TFA (FIG. 5) compared toabsence of TFA (FIG. 3) at 1 kV. Thus addition of trifluoroacetic acidcatalyst showed only slight improvement in the formation of the esterproduct.

Example 4 Electrospray Chemical Synthesis with Variable Cone Voltage inthe presence of TFA

8.8 mg of 2-pyridylacetic acid hydrochloride was dissolved in 19.72 mlof methanol and ESI-MS spectrum were generated at a constant capillaryvoltage of 3.00 kV and a variety of cone voltage values, morespecifically 30, 80 and 100 V, in the presence of TFA, as can be seen inFIGS. 6A, B and C, respectively. Acids are commonly used as a catalystfor reactions between acid and alcohol. The results showed that presenceof a catalyst did not improve the production of an ester at a high conevoltage.

Example 5 Electrospray Chemical Synthesis with Variable CapillaryVoltage in the presence of Ethanol

8.8 mg of 2-pyridylacetic acid hydrochloride was dissolved in 19.72 mlof methanol and ESI-MS spectrum were generated at a constant conevoltage of 40 V and a variety of capillary voltage values, morespecifically 1.00, 3.00 and 5.00 kV, in the presence of ethanol, as canbe seen in FIGS. 7A, B and C, respectively. Protonated 2-pyridalaceticacid gives signal at 138 (n+1) while 2-pyridalacetic acid ethyl estershows the corresponding signal at 166 (n+1). The signal corresponding toethyl ester increases as the capillary voltage is increased from +1 kVto +4 kV.

Example 6 Electrospray Chemical Synthesis with Variable Cone Voltage inthe presence of Ethanol

8.8 mg of 2-pyridylacetic acid hydrochloride was dissolved in 19.72 mlof methanol and ESI-MS spectrum were generated at a constant capillaryvoltage of 3.00 kV and a variety of cone voltage values, morespecifically 30, 40, 80 and 100 V, in the presence of ethanol, as can beseen in FIGS. 8A, B, C and D, respectively. Ethyl esters decompose athigh cone voltage (>40 V).

Example 7 Formation of Methyl Ester by Electrospray Ionization

A stock solution was prepared by dissolving 2-pyridyl acetic acidhydrochloride (8.8 mg) in 20 ml of methanol. A portion of the abovestock solution was placed in a 250 μL Hamilton gas tight syringe. Thesolution was infused at the rate of 10 μL/min to Micromass QuattroUltima ES-MS system using a Harvard syringe pump. A signal correspondingto the 2-pyridyl acetic acid methyl ester was observed at 152 (n+1)along with 2-pyridyl acetic acid at 138 (n+1) and a 1:1 complex of2-pyridyl acetic acid-methanol at 170 (n+1). The experiment was alsoconducted using 2-pyridylacetic acid hydrochloride in methanol and TFAsolution to observe the effect of acid catalysis on the formation of theester in the electrospray. The maximum intensity of the signalcorresponding to the ester was at the following conditions: Conevoltage=30 volts and capillary voltage 4 KV.

Example 8 Formation of Ethyl Ester by Electrospray Ionization

A stock solution was prepared by dissolving 2-pyridyl acetic acidhydrochloride (8.4 mg) in 21 ml of anhydrous ethanol. A portion of theabove stock solution was placed in a 250 μL Hamilton gas tight syringe.The solution was infused at the rate of 10 μL/min into a MicromassQuattro Ultima ES-MS system using a Harvard syringe pump. A signalcorresponding to the 2-pyridyl acetic acid ethyl ester was observed at166 (n+1) along with 2-pyridyl acetic acid at 138 (n+1) and a 1:1complex of 2-pyridyl acetic acid-ethanol at 184 (n+1). The maximumintensity of the signal corresponding to the ethyl ester was at thefollowing conditions: Cone voltage=30 volts and capillary voltage 3 KV.

Example 9 Formation and Disproportion of Esters by ElectrosprayIonization

A stock solution was prepared by dissolving 2-pyridyl acetic acidhydrochloride (6 mg) in 3.4 ml of 2-propanol. A portion of the abovestock solution was placed in a 250 μL Hamilton gas tight syringe. Thesolution was infused at the rate of 10 μL/min into a Micromass QuattroUltima ES-MS system using a Harvard syringe pump. A signal correspondingto the 2-pyridyl acetic acid isopropyl ester was observed at 180 (n+1)along with 2-pyridyl acetic acid at 138 (n+1) and 2-pyridyl acetic acidmethyl ester at 152 (n+1) (FIG. 9).

Example 10 Formation and Disproportion of Esters by ElectrosprayIonization

A stock was prepared by dissolving 2-pyridyl acetic acid hydrochloride(3.5 mg) in 3 ml of 1-butanol. A portion of the above stock solution wasplaced in a 250 μL Hamilton gas tight syringe. The solution was infusedat the rate of 10 μL/min into a Micromass Quattro Ultima ES-MS systemusing a Harvard syringe pump. A signal corresponding to the 2-pyridylacetic acid butyl ester was observed at 194 (n+1) along with 2-pyridylacetic acid at 138 (n+1) and 2-pyridyl acetic acid methyl ester at 166(n+1) (FIG. 11).

Example 11 Reduction Reaction by Electrospray Ionization

A stock solution was prepared by dissolving 5-bromo-2-nitropyridine (7mg) in 5.2 ml of methanol. A portion of the above stock solution wasplaced in a 250 μL Hamilton gas tight syringe. The solution was infusedat the rate of 10 μL/min into a Micromass Quattro Ultima ES-MS systemusing a Harvard syringe pump. Formation of a product showed a strongdependence on ES conditions such as cone voltage, source temperature anddesolvation temperature. A signal corresponding to the5-bromo-2-aminopyridine was observed at 173 and 175 (n+1) and along with5-bromo-2-nitropyridine at 203 and 205 (n+1) and 235; 237(n+MeOH+1).

The product was observed at the following conditions; Capillaryvoltage=3.5; cone voltage=100; source temperature=150° C.; anddesolvation temperature=500° C.

The reduction product has signals at 173 and 175 along with the startingmaterial 203 and 205. (The signal at 188 and 190 is the reducedintermediate.)

Decreasing cone voltage from 100 to 60 volt completely abolished reducedproduct. The spectra of this example can be seen in FIG. 9.

Example 12 Aldol Condensation by Electrospray Ionization

A stock solution was prepared by dissolving 4-pyridinecarboxaldehyde (9mg) in 4.5 ml of acetone. A portion of the above stock solution wasplaced in a 250 μL Hamilton gas tight syringe. The solution was infusedat the rate of 10 μL/min into a Micromass Quattro Ultima ES-MS systemusing a Harvard syringe pump. Formation of product was stronglydependent on ES conditions such as cone voltage, source temperature anddesolvation temperature. A signal corresponding to the4-hydroxy-4-(pyridin-4-yl)butan-2-one was observed at 166 (n+1). Thesignal due to the product disappear at capillary voltage below 3.5 KV(FIG. 10).

Example 13 Catalysis by Electrospray Ionization

A stock solution was prepared by dissolving 2-amino-5-bromopyridine (13mg) in a mixture of acetic acid (3.05 g) and acetic anhydride (3.14 g).A portion of the above stock solution was placed in a 250 μL Hamiltongas tight syringe. The solution was infused at the rate of 10 μL/mininto a Micromass Quattro Ultima ES-MS system using a Harvard syringepump. Formation of product was strongly dependent on ES conditions suchas cone voltage, source temperature and desolvation temperature.Formation of the product showed strong dependence on ES conditions suchas cone voltage, source temperature and desolvation temperature. Asignal corresponding to the N-(5-bromopyridin-2-yl)acetamide wasobserved at 215 and 217 (n+1) along with 1:1 complex of2-amino-5-bromopyridine and acetic acid at 275 and 277(n+1). The ratioof the N-(5-bromopyridin-2-yl)acetamide and 1:1 complex of2-amino-5-bromopyridine and acetic acid was strongly dependent upon conevoltage, capillary voltage, source temperature, and desolvationtemperature. The spectra of this example can be seen in FIG. 13.

Example 14 Amide Formation by Electrospray Ionization

A stock solution was prepared by dissolving a mixture of(2S)-2-amino-3-(4-(hydroxyhydrophosphoryl)phenyl)propanoic acid and(2S)-2-amino-3-(4-(hydroxyhydrophosphoryl)phenyl)propanoic acid methylester in an aqueous solution of diethylamine. A portion of the abovestock solution was placed in a 250 μL Hamilton gas tight syringe. Thesolution was infused at the rate of 10 μL/min into a Micromass QuattroUltima ES-MS system using a Harvard syringe pump. Formation of theproduct showed strong dependence on ES conditions such as cone voltage,source temperature and desolvation temperature. A signal correspondingto the 4-((S)-2-amino-3-(diethylamino)-3-oxopropyl)phenylphosphinic acidwas observed at 183 (n−1) along with(2S)-2-amino-3-(4-(hydroxyhydrophosphoryl)phenyl)propanoic acid at 228(n−1). This is an example of catalysis of amide formation byelectrospray. The spectra for this example can be seen in FIG. 14.

Example 15 Hydrolysis of Esters by Electrospray Ionization

A stock solution was prepared by dissolving 3-formylphenoxyacetic acid(4 mg) in 4.3 ml of methanol. A portion of the above stock solution wasplaced in a 250 μL Hamilton gas tight syringe. The solution was infusedat the rate of 10 μL/min into a Micromass Quattro Ultima ES-MS systemusing a Harvard syringe pump. Formation of product showed strongdependence on ES conditions such as cone voltage, source temperature anddesolvation temperature. A signal corresponding to the2-hydroxy-benzaldehyde was observed at 121 (n−1) (FIG. 15).

Example 16 Synthesis of Secondary Amine by Electrospray Ionization

A stock solution was prepared by dissolving 2-nitro-5-bromopyridine (8mg) in 5 ml of methanol. A portion of the above stock solution wasplaced in a 250 μL Hamilton gas tight syringe. The solution was infusedat the rate of 10 μL/min into a Micromass Quattro Ultima ES-MS systemusing a Harvard syringe pump. Formation of product showed strongdependence on ES conditions such as cone voltage, source temperature anddesolvation temperature. A signal corresponding to thebis(5-bromopyridin-2-yl)amine was observed at 328, 330, and 332 (n+1)confirming two bromine atom in the molecule. The spectra for thisexample can be seen in FIG. 16.

Example 17 Synthesis of Imine by Electrospray Ionization

A stock solution was prepared by dissolving 4-bromoaniline (14 mg) and2-formylphenoxyacetic acid in a solvent system comprising 3.7 ml ofwater and 5.4 ml of methanol. A portion of the above stock solution wasplaced in a 250 μL Hamilton gas tight syringe. The solution was infusedat the rate of 10 μL/min into a Micromass Quattro Ultima ES-MS systemusing a Harvard syringe pump. Formation of the product showed strongdependence on ES conditions such as cone voltage, source temperature anddesolvation temperature. A signal corresponding to the2-(2-((4-bromophenylimino)methyl)phenoxy)acetic acid was observed at328, 330, and 332 (n+1) confirming two bromine atom in the molecule.

Example 18 Synthesis of Monoethyl and Diethyl Acetal by ElectrosprayIonization

A stock solution was prepared by dissolving 2-formylphenoxyacetic acid(5 mg) in 3.1 ml of ethanol. A portion of the above stock solution wasplaced in a 250 μL Hamilton gas tight syringe. The solution was infusedat the rate of 10 μL/min into a Micromass Quattro Ultima ES-MS systemusing a Harvard syringe pump. Formation of product was stronglydependent on ES conditions such as cone voltage, source temperature anddesolvation temperature. A signal corresponding to2-(2-(diethoxymethyl)phenoxy)acetic acid was observed at 253 (n−1) inthe negative mode. The product is favored at high desolvationtemperature. High cone voltage, high source and desolvation temperaturefavors 2-(2-(ethoxy(hydroxy)methyl)phenoxy)acetic acid 225 (n−1). Thespectra for this example can be seen in FIG. 17.

Example 19 Synthesis of Dimethyl Acetal by Electrospray Ionization

A stock solution was prepared by dissolving 2-formylphenoxyacetic acid(4 mg) in 2.5 ml of methanol. A portion of the above stock solution wasplaced in a 250 μL Hamilton gas tight syringe. The solution was infusedat the rate of 10 μL/min into a Micromass Quattro Ultima ES-MS systemusing a Harvard syringe pump. Formation of product was stronglydependent on ES conditions such as cone voltage, source temperature anddesolvation temperature. A signal corresponding to2-(2-(dimethoxymethyl)phenoxy)acetic acid was observed at 225 (n−1) inthe negative mode. The spectra for this example can be seen in FIG. 18.

Example 20 Synthesis of Carboxylic Acid by Oxidation of Alcohol byMethods of Electrospray Ionization

A stock solution was prepared by dissolving 2-formylphenoxyacetic acid(4 mg) in 2.5 ml of methanol. A portion of the above stock solution wasplaced in a 250 μL Hamilton gas tight syringe. The solution was infusedat the rate of 10 μL/min into a Micromass Quattro Ultima ES-MS systemusing Harvard syringe pump. Formation of the product was stronglydependent on ES conditions such as cone voltage, source temperature anddesolvation temperature. A signal corresponding to2-(carboxymethoxy)benzoic acid was observed at 196 (n−1) in the negativemode at low desolvation temperature. Increasing the desolvationtemperature above 400 completely eliminated the signal due to oxidizedproduct.

Example 21 Oxidation of Alcohol by Electrospray Ionization

A stock solution is prepared by dissolving 4-(hydroxymethyl)benzoic acidin water. A portion of the above stock solution is added to a 250 μLHamilton gas tight syringe. The solution is infused into a MicromassQuattro Ultima ES-MS system using Harvard syringe pump at the rate of 10μL/min. The product is observed in negative mode.

Example 22 Reduction of Azide by Electrospray Ionization

A stock solution is prepared by dissolving 4-(azidomethyl)pyridine inwater. A portion of the above stock solution is added to a 250 μLHamilton gas tight syringe. The solution is infused at the rate of 10μL/min into a Micromass Quattro Ultima ES-MS system using Harvardsyringe pump. The product is observed in positive mode.

Example 23 Cyclization Reactions: Formation of Aziridine by ElectrosprayIonization

A stock solution is prepared by dissolving 2-aminoethanol in water. Aportion of the above stock solution is added to a 250 μL Hamilton gastight syringe. The solution is infused at the rate of 10 μL/min into aMicromass Quattro Ultima ES-MS system using a Harvard syringe pump at.The product is observed in positive mode.

Example 24 Alkylation of amine

A stock solution is prepared by dissolving 5-bromo-2-nitropyridine andcyclopentylboronic acid in water. A portion of the above stock solutionis added to a 250 μL Hamilton gas tight syringe. The solution is infusedat the rate of 10 μL/min into a Micromass Quattro Ultima ES-MS systemusing a Harvard syringe pump. The product is observed in positive mode.

Example 25 Suzuki Reaction

A stock solution is prepared by dissolving 5-bromo-2-nitropyridine andcyclopentylboronic acid and traces of palladium catalyst in water. Aportion of the above stock solution is added to a 250 μL Hamilton gastight syringe. The solution is infused at the rate of 10 μL/min into aMicromass Quattro Ultima ES-MS system using a Harvard syringe pump. Theproduct is observed in positive mode.

Example 26 Heck Reaction

A stock solution is prepared by dissolving 4-iodophenylalanine andmethylacrylate and traces of palladium catalyst in methanol. A portionof the above stock solution is added to 250 μL Hamilton gas tightsyringe. The solution is infused at the rate of 10 μL/min into aMicromass Quattro Ultima ES-MS system using a Harvard syringe pump. Theproduct is observed in positive mode.

Example 27 Alkylation Reaction

A stock solution is prepared by dissolving 3-hydroxy pyridine in1-bromobutane. A portion of the above stock solution is added to a 250μL Hamilton gas tight syringe. The solution is infused at the rate of 10μL/min into a Micromass Quattro Ultima ES-MS system using a Harvardsyringe pump. The product is observed in positive mode.

Example 28 Multi-Step Reaction

2-pyridylacetic acid hydrochloride was dissolved in 1-butanol and ES-MSspectrum were generated at constant capillary voltage of 3.5 kV andvariety of cone voltage values, more specifically 100 and 20 V, as canbe seen in FIGS. 19A and 19B respectively. The esterification processwas favored at a high cone voltage. An ethyl ester resulting fromelimination reaction from butyl ester was also observed. Thus, an ethylester was produced by a two-step reaction from 2-pridylacetic acid. Noproduct was observed at cone voltage below 20V.

Example 29 Elimination Reaction

2-pyridylacetic acid hydrochloride was dissolved in 2-propanol and ES-MSspectrum were generated at constant capillary voltage of 3.5 kV and conevoltage of 97V, as can be seen in the FIG. 20. The esterificationprocess was favored at a high cone voltage. A methyl ester resultingfrom an elimination reaction was observed. A propyl ester was alsoobserved.

I/We claim:
 1. A method of preparing and recovering a reaction product,comprising causing a chemical reaction by passing a reactant through anelectrospray to provide a reaction mixture and recovering said reactionproduct from the reaction mixture, wherein said chemical reactioncomprises a formation of a covalent bond.
 2. A method as claimed inclaim 1, wherein said reaction product is in a quantity greater than 1milligram.
 3. A method of as claimed in claim 1, wherein said covalentbond comprises a carbon-carbon, carbon-oxygen, carbon-hydrogen,oxygen-hydrogen, carbon-phosphorous, phosphorous-oxygen,phosphorous-nitrogen, carbon-sulfur, carbon-halogen, carbon-nitrogen,carbon-boron, sulfur-nitrogen, carbon-silicon, oxygen-silicon,oxygen-oxygen, oxygen-nitrogen, nitrogen-nitrogen, sulfur-sulfur, orcarbon-selenium bond.
 4. A method as claimed in claim 1, wherein saidreaction product is an oxidation reaction product, and said chemicalreaction comprises passing a reactant through an electrospray to providea reaction mixture and recovering said reaction product from thereaction mixture.
 5. A method as claimed in claim 1, wherein saidreaction product is a reduction reaction product, and said chemicalreaction comprises passing a reactant through an electrospray to providea reaction mixture and recovering said reaction product from thereaction mixture.
 6. A method as claimed in claim 1, wherein saidreaction product is an aldol condensation reaction product, and saidchemical reaction comprises passing an enol compound and a carbonylcompound through an electrospray to provide a reaction mixture andrecovering said reaction product from the reaction mixture.
 7. A methodas claimed in claim 1, wherein said reaction product is an amide, andsaid chemical reaction comprises passing a carboxylic acid and an aminethrough an electrospray to provide a reaction mixture and recoveringsaid amide from the reaction mixture.
 8. A method as claimed in claim 1,wherein said reaction product is a secondary amine, and said chemicalreaction comprises passing a nitro compound through an electrospray toprovide a reaction mixture and recovering said secondary amine from thereaction mixture.
 9. A method as claimed in claim 1, wherein saidreaction product is an imine, and said chemical reaction comprisespassing an amine and an aldehyde through an electrospray to provide areaction mixture and recovering said imine from the reaction mixture.10. A method as claimed in claim 1, wherein said reaction product is analkyl amine, and said chemical reaction comprises passing an amine andan alkyl halide through an electrospray to provide a reaction mixtureand recovering said alkyl amine from the reaction mixture.
 11. A methodas claimed in claim 1, wherein said reaction product results from thehydrolysis of an ester, and said chemical reaction comprises passing anester through an electrospray to provide a reaction mixture andrecovering said reaction product from the reaction mixture.
 12. A methodas claimed in claim 1, wherein said reaction product is a mono or diacetyl, and said chemical reaction comprises passing an alcohol and analdehyde through an electrospray to provide a reaction mixture andrecovering said mono or di acetyl from the reaction mixture.
 13. Amethod as claimed in claim 1, wherein said reaction product is analcohol and carboxylic acid, and said chemical reaction comprisespassing an ester through an electrospray to provide a reaction mixtureand recovering said alcohol and carboxylic acid from the reactionmixture.
 14. A method as claimed in claim 1, wherein said reactionproduct is an alcohol oxidation product, and said chemical reactioncomprises passing an alcohol through an electrospray to provide areaction mixture and recovering said alcohol oxidation product from thereaction mixture.
 15. A method as claimed in claim 1, wherein saidreaction product results from the alkyation of an amine, and saidchemical reaction comprises passing an amine and alkyl halide through anelectrospray to provide a reaction mixture and recovering said reactionproduct from the reaction mixture.
 16. A method as claimed in claim 1,wherein said chemical reaction comprises preparing and recovering aSuzuki reaction product, by passing aryl- or vinyl-boronic acid with anaryl- or vinyl-halide through an electrospray to provide a reactionmixture and recovering said reaction product from the reaction mixture.17. A method as claimed in claim 1, wherein said chemical reactioncomprises preparing a Heck reaction product, by passing aryl- orvinyl-halide with an alkene, through an electrospray to provide areaction mixture and recovering said reaction product from the reactionmixture.
 18. A method as claimed in claim 1, wherein said reactionproduct comprises an ester, and said chemical reaction comprises passingan acid and an alcohol through an electrospray to provide a reactionmixture and recovering said reaction product from the reaction mixture.19. A method as claimed in claim 1, wherein said chemical productcomprises a cyclized molecule and said chemical reaction comprisespassing a cyclizable molecule through an electrospray to provide areaction mixture and recovering said reaction product from the reactionmixture.
 20. The method of claim 1 wherein the capillary voltage of theelectrospray is between 1.0 to 4.0 kV.
 21. The method according to claim1, wherein the reaction product is enriched by passing the reactionmixture through a second electrospray.